The present invention relates to an extended release formulation of clonidine. Specifically, it relates to an oral dosage form of clonidine which provides a release period suitable for twice or three times daily dosing while exhibiting good bioavailability.
Clonidine is a well known and widely used alpha-adrenergic agonist. Clonidine is effective in the treatment of a wide range of clinical disorders including hypertension; prophylaxis of common migraine headaches; subduing motor tics such as in Tourette's syndrome; and decreasing hyperactivity, impulsivity and over excitability in Attention Deficit Hyperactivity Disorder, manic states and many other clinical syndromes which involve over arousal.
Clonidine is given in either an oral dose in tablet form three to four times per day or via a transdermal patch. In the oral formulation currently in use, clonidine is almost completely absorbed from the gastrointestinal tract, but it is subject to rapid liver metabolism. The biological half-life ranges from about four to six hours after oral administration, with wide interpatient variability.
The traditional oral formulations of clonidine have disadvantages. The oral dose has the main side-effect of sedation, particularly about an hour after the given dose when the patient may become transiently sedated, even falling asleep. Because the half-life of this dosage form of clonidine is only about four to six hours, there is also the problem of the drug wearing off with some rebound hyperarousal. This can occur in the middle of the night causing insomnia, and even nightmares in some cases. Such side effects have limited the practical usefulness of oral clonidine.
A transdermal patch has partially solved these problems by providing a more stable serum level (U.S. Pat. No. 4,201,211). The transdermal patch, however, has the disadvantage of producing a high rate of contact dermatitis. There are also problems with patch adherence to the skin in humid environments and with active individuals. The patch may need replacement after extended swimming or exertion. The inconvenience of the patch can lead to reduced patient compliance.
For the foregoing reasons, there is a need for a clonidine formulation which is capable of stable therapeutic effects by maintaining a constant serum level for an extended period in order to avoid the "peak and trough" side effects of transient sedation at peak serum levels and rebound exacerbation of symptoms at trough levels. The clonidine formulation should be easy and inexpensive to manufacture and convenient for the patient to use.